Antifungal dieneoic alcohols

ABSTRACT

Dieneoic acid delta -methylene-1-cyclopentene-1-pentanoic acid is obtained by reacting cyclopentanone with one chemical equivalent of methylsulfinylmethide alkali metal salt in dimethylsulfoxide. Lithium aluminum hydride reduction of the acid provides Epsilon -methylene-1-cyclopentene-1-pentanol. The acid, metal salts thereof, lower alkyl esters, and the alcohol are effective antifungal agents.

United States Patent Comer et al.

[111 3,903,174 51 Sept, 2, 1975 ANTIFUNGAL DIENEOIC ALCOHOLS Inventors:William T. Comer; James W.

Rayburn; Davis L. Temple, all of Evansville, Ind.

Mead Johnson & Company, Evansville, Ind.

Filed: Oct. 21, 1974 Appl. No.: 516,303

Related US. Application Data Division of Ser. No. 300,942, Oct. 26,1972, Pat. No. 3,853,949, which is a continuation-in-part of Ser. No.246,309, April 2], 1972, abandoned.

Assignee:

US. Cl 260/617 R Int. Cl. C07C 27/00 Field of Search 260/617 RReferences Cited UNITED STATES PATENTS 5/l952 Linn 260/617 R 3,214,45910/1965 Miller 260/468 OTHER PUBLICATIONS V. N. Belov et al., Chem.Abst., Vol. 62, N0. 3946b, (I965), (Zh. Obshoh Khim 34(10), 3432-3435,(1965).

Primary ExaminerBernard Helfin Assistant Examiner-James H. ReamerAttorney, Agent, or FirmRobert H. Uloth; Robert E,-

Carnahan [5 7] ABSTRACT Dieneoic acid S-methylenel -cyclopentenel 2Claims, No Drawings ANTIFUNGAL DIENEOIC ALCOHOLS CROSS-REFERENCE TORELATED APPLICATIONS This application is a division of co-pending U.S.application Ser. No. 300,942, filed Oct. 26, 1972 now US, Pat. No.3,853,949, which is a continuation-inpart of then co-pending applicationSer. No. 246,309, filed April 21, 1972, now abandoned.

BACKGROUND OF THE INVENTION This invention is concerned with carboncompounds and in particular olefinic carboxylic acids and a process formaking same. It is further concerned with alkyl ester derivatives of theolefinic acids and alkali metal salts thereof.

The compounds of the present invention are antifungal agents.

SUMMARY OF THE INVENTION This invention relates to new diene carboxylicacids of Formula I and to a process for their preparation. The inventionfurther relates to esters and non-toxic pharmaceutically acceptablemetal salts of the acids of Formula I and to alcohols of Formula IIobtained by reduction of the acid. These substances are useful asantifugal agents.

In the above formulas, R signifies hydrogen or methyl with the provisothat whenever R is methyl the R-cyclopentenyl radical is selected fromthe group consisting of 3methyl-l-cyclopentenyl and4-methyll-cyclopentenyl; and R represents hydrogen or lower alkyl. Bythe term lower alkyl" it is meant that the carbon chains which comprisethis group include both straight and branch chain carbon radicals offrom I to 4 carbon radicals of from 1 to 4 carbon atoms inclusive suchas methyl, ethyl, propyl, isopropyl, l-butyl, lmethylpropyl,2-mcthylpropyl, and tert.-butyl.

It will be apparent to those skilled in the art that both geometricaland optical stereoisomeric forms of the compounds of Formula I wherein Ris methyl are possible, and it is to be understood that this inventioncomprehends all forms thereof.

Diene acids of Formula I wherein R is hydrogen and R is as above areobtained in accord with the process of the present invention by reactinga member of the group consisting of cyclopentanone,3-methylcyclopentanone, and Z-cyclopentylidene cyclopentanone, with onechemical equivalent of a methylsulfinylmethide alkali metal salt such assodium methylsulfinylmethide, potassium methylsulfinylmethide or lithiummethylsulfinylmethide in excess dimethyl sulfoxide. The reaction ispreferably carried out with one chemical equivalent of sodiummethylsulfinylmethide to that of the ketone at -25C. For purposes ofrecovery, the reaction mixture is quenched in a water immiscible-organicsolvent such as methylene chloride or acid which is purified byconventional techniques such as distillation and crystallization.

The fact that the diene acids of the present invention are obtainedaccording to the above method by reaction of a cyclopentanone or the2-cyclopentylidene cyclopentanone products with methylsulfinyl carbanionin dimethylsulfoxide is surprising and highly unex pected. For instance,E. J. Corey, et al., J. Am. Chem. Soc, 84, 866 (I962), 87, 1345 (1965),report that under similar conditions cyclohexanone and cycloheptanoneyield only corresponding enolate anions or beta-hydroxysulfoxideproducts. The reaction of methylsulfinyl carbanion with a cycloalkylketone in dimethylsulfoxide to provide diene carboxylic acids is believed to be quite specific in nature and limited to cyclopentanone andits 3alkyl substituent. Reaction of Z-methylcyclopentanone withdimethylsulfoxide provides the corresponding dienoic acid in traceamounts. Cycloalkyl ketones such as cyclobutanone,2,5-dimethylcyclopentanone, and 3,4-dimethylcyclopcntanone do not givediene carboxylic acids analogous to those of Formula I under theconditions of the procedure described herein.

Alkali metal salts of the diene carboxylic acids of FORMULA II Formula Ican be obtained directly by utilizing the appropriate alkali metalmethylsulfinyl carbanion. Other metal salts can beprcpared byneutralizing the free acid with bases of metalic cations. By way ofexample, there can be mentioned such salts as the sodium, potassium,lithium, aluminum, copper, and zinc salts of 8-methylenel -cyclopentenel-pentanoic acid.

The lower alkyl esters of the present invention are obtained by reactingthe diene carboxylic acid with N,N'-carbonyldiimidazole and theappropriate alcohol under basic catalysis. Esters can also be obtainedby re acting the diene carboxylic acid with an excess of the alcohol inether solvent employing a catalyticarnount of perchloric acid at 25C.

Reduction of the dienoic acids with lithium aluminum hydride providesthe corresponding alcohols of Formula II.

The compounds of Formulas I and II possess good antifungal propertieswhich can be readily demonstrated by the disc-plate method. According tothis well-known method, Sabouraud dextrose agar is inoculated withsuspensions of various pathogenic dermatophytes and related fungi andthe inoculated agar allowed to solidify in sterile petri dishes. Asolution of the test agent is added to filter paper discs and the discsplaced on the agar surface of the plate. The plates are then incubatedat 30C. and zones of inhibition are measured for various drugconcentrations and compared with standard reference agents such asundecylinic acid. The lowest culture is determined by varying the drugconcentration and is designated as the minimal inhibitory concentration(MIC). The following table is illustrative of the MIC values obtainedfor 8-methy1ene-1-cyclopentene-l-pentanoic acid and the ethyl esterthereof compared to undecylenic acid.

TABLE I IN VITRO ANTIFUNGAL ACTIVITY Minimum Inhibitory Undecylenic AcidConcentration (meg/ml.)

Micmsporum auduuini ATCC 9079 12.5 Micruxporum canix ATCC 10241 25TricImp/zymn menlagruphylax 12.5 (gypseum) ATCC 9129 v Triclzoplrvmnnianlagrop/rv[ex 50 (interdigitalc) ATCC 9972 Trizhvpllymnmz'magmplrv10s 25 (astcroides) ATCC 8757 Candida alhicanx ATCC 10231 1008-Methylene-1 -cyclopcntcnc-1-pcntanoic Acid Micmxporum auduuini ATCC9079 25 Micruxpvrum canis ATCC 10241 25 'l'riclmpliymn menIagrophytex 25(gypscum) ATCC 9129 Triu/wphymn "It'llll lgrQp/[YIPS 25 (interdigitale)ATCC 9972 'Iriclmphylan menlugmp/iymr 25 (asteroides) ATCC 8757 Candidaalbir'alm' ATCC 10231 100 Ethyl S-mcthylcne-l-cyclopcntene-1- penlanoatcMicros-porn! audimini ATCC 9079 25 Microxpurum ((IlliS ATC C 10241 50'l'riz'liophymn manlagropli \'1z'.\' 25 (gypscum) ATCC 9129 TricImp/rvmnmanlagropliytax 50 (interdigitalc) ATCC 9972 'I'riclmphylonnicnlagmpllyles "5 (ustcroides) ATCC 8757 Candida alhicans ATCC 10231100 the preferred concentration of the compounds identified by FormulasI and II ranged from 1 to 20%.

The compounds of the present invention are relatively non-toxiccompounds. In mice, for instance, S-methylene-l-cyclopentene-l-pentanoicacid and ethyl fi-methylene-1-cyclopentene-'l-pentanoate have an ALD ofgreater than 2,000 trig/kg. body weight upon oral administration.

The following examples are given by way of illustration and are not tobe construed as limitations of this invention.

, EXAMPLE 1 8-Methy1ene-1'-cyclopentenel -pentanoic acid Sodiummethylsulfinyl carbanion is prepared under nitrogen by adding a 57%mineral oil dispersion of sodium hydride (54.0 g., 1.28 mole) to 250 ml.of dry dimethyl sulfoxide with stirring and then slowly increasing thetemperature of the suspension to 71C. where it is maintained untilhydrogen is no longer evolved. The gray mixture of sodium methylsulfinylcarbanion is then immediately cooled to 25C. and cyclopentanone (100.0g., 1.19 mole) addeddropwise thereto. The reaction of cyclopentanonewith the carbanion is slightly exothermic and is moderated in an icebath for 0.5 hr. The reaction mixture is stirred at 25C. for anadditional 5 hr. period, poured into 2.1 of chilled 1:1 methylenechloride-ether in an ice bath, refrigerated overnight, and the finelydivided precipitated product is collected and washed with 9:1ether-methylene chloride. Air drying provides 197 g. of the sodium saltof S-methylene-1-cyclopentene-1-pentanoic acid (62.8 g., 59%) as anorange oil which solidifies on standing. Purification of the acid iscarried out by conversion to its sodium salt, followed by neutralizationto provide analytically pure S-methylene- 1 -cyclopentenel -pentanoicacid as white crystals M.P. 43.556.5C. (corr.); ultraviolet absorptionspectrum in ethanol exhibits a single band at 237 nm (6 max 16,300).

Analysis. Calcd. (percent) for C H O C, 73.30; H, 8.95. Found (percent):C, 73.20; H, 8.83.

NMR 8 (ppm) (CDC1 tetramethylsilane ref): 1.88 [m, 6H, (CH 2.38 [m, 6H,(CH C=)3], 4.98 (s, 2H, =CH 5.87 (s, 1H, =CH), 9.12 (s, 1H, CO H).

Infrared (pelleted with K Br): 1720 cm." (C=C), 1620 cm. (C=C), 1580 cm.(C=C).

EXAMPLE 2 Ethyl S-methylenel cyclopentene l -pentanoateN,N'Carbonyldiimidazole l 1.3 g., 0.07 mole) is added in small portionsto 8-methylene-l-cyclopentene-1pentanoic acid (1.1.6 g., 0.065 mole) in50 ml. dry tetrahydrofuran. After carbon dioxide evolution has ceased,50 ml. of absolute ethanol containing a catalytic amount of sodiumethoxide is added, the mixture stirred at room temperature for 2 hr. andthen most of the solvent evaporated under reduced pressure, The residuethus obtained is dissolved in ether, washed with water, and coldsolutions of 1 N. NaOH and l N. HCl. Drying the ethereal extract over amagnesium sulfate and evaporating in vacuo provides 13.5 g. of the esteras a yellow oil. Distillation of the yellow oil yields" analyticallypure ethyl 8-methylene-1- cyclopentene-l-pentanoate as a pale yellow oilhaving a boiling point of 71C. at 0.2 mm Hg n 1.484; infrared filmexhibits carbonyl absorption at 1740 emf.

Analysis. Calcd. (percent) for C H O C, 74.96; H, 9.68. Found (percent):C, 74.88; H, 9.77.

NMR 8 (ppm) (CDC1 tetramethylsilane ref.), 1.24 (t, 3H, CH 1.88[m, 6H,(CI-[Q 2.38[m, 6H, (CI-I 4.13 (8, 2H, CH CH 4.98 (s, 21-1, =CH 5.87 (s,1H, =CH).

Infrared (film) 1730 cm. (C=C), 1620 cm. (C=C), 1590 emf (C=C).

' By substitution of ethanol in the above procedure with an equimolarweight of isopropyl alcohol, n-butyl alcohol, or tert.-butyl alcoholwith catalytic amounts of the sodium salts thereof, there is producedrespectively:

isopropyl S-methylenel -cyclopentene- 1 -pentanoate, n-butylfi-methylene- 1 -cyclopentenel -pentanoate, tert.-butyl' S-methylene- 1-cyclopentene- 1 -pentanoate.

EXAMPLE 3 Reaction of 3-methylcyclopentanone with sodium methylsulfinylcarbanion By substituting an equimolar weight of3-methylcyclopentanone'in the procedure of Example 1 for cyclopentanone,there is produced an isomeric mixture of S-methylencl-cyclopentene- 1-pentanoate along with a substantial amount of 3-methylglutaric acid.Esterification of this mixture of acids according to the procedure ofExample 2 produces the corresponding ethyl esters. Purification iscarried out by fractional distillation through a 6 inch Vigreaux columnto provide first the side-product diethyl 3-methylglutarate, b.p. 82C.at 0.2 mm Hg, and then the ester fraction having a boiling point of l16C. at 0.3 mm Hg., n 1.3074. According to vapor phase chromatographicanalysis and nmr spectral data, the ester product consists of an equalmixture of both isomers of ethyl B-methyl-S- methylene-1-(3-methylcyclopentene 1 -pentanoate and ethyl B-methyl-S-methylene-1-(4-methylcyclopentene)-l-pentanoate illustrated by Formula 111 and FormulaIV respectively.

EXAMPLE 4 Reaction of 2-cyclopentylidene cyclopentanone with sodiummethylsulfinyl carbanion 2-Cyclopentylidene cyclopentanone (6.4 g.,0.043 mole) obtained according to the method of French, et al., J. Am.Chem. Soc., 71, 3702 (1949) is added in the manner of the procedure ofExample 1 to sodium methylsulfinyl carbanion obtained from 1.94 g. of a53% mineral oil of dispersion of sodium hydride in dimethyl sulfoxide.There is thus obtained 5.6 g., of the sodium salt ofS-methylene-l-cyclopentene-l-pentanoic acid which, if desired, canfurther be neutralized to provide the free acid in a 26% yield.

By substitution of 2-cyc1opentylidene cyclopentanone in the aboveprocedure with an equimolar weight of2-(3-methylcyclopentylidene)-3-methylcyclopentanone there is producedB-methyl-6-methylene-1-( 3- methylcyclopentene)-l-pentanoic acid andB-methyL S-methylenel -(4-methylcyclopentene 1 -pentanoic acid.

EXAMPLE 5 e-Methylene- 1 -cyclopentenel-pentanol fi-Methylene- 1-cyclopentenel -pentanoic acid (60. 3 g., 0.336 mole) in 100 m1. of drytetrahydrofuran is added to lithium aluminum hydride (25.5 g., 0.672

mole) in 500 ml. of dry tetrahydrofuran under nitrogen with cooling at0C. The mixture is refluxed with stirring 4 hrs., cooled to 0C. anddecomposed by sequential addition of 25 ml. water in 50 ml.tetrahydrofuran, 25 ml. 15% sodium hydroxide, and 75 ml. water andfiltered. The filtrate dried over magnesium sulfate and concentratedunder reduced pressure provides 50.9 g. (91% yield) of pure productaccording to nmr data. The product can be distilled with considerablepolymerization, and has a boiling point of 82C. at 0.1 mm Hg.

Analysis. Calcd. for C H O (percent): C, 79,46; H, 10.91. Found(percent): C, 79.30; H, 10.96.

NMR 8 (ppm) (CDCl tetramethylsilane ref.): 5.77 (s, 1H, =CH); 4.90 (S,2H, =CH 3.63 (t, 2H, CH OH).

The in vitro antifungal activity of e-methylene-lcyclopentene-l-pentanolby the disc-plate method is as follows:

Minimum Inhibitory Test Organism Concentration (meg/ml.)

Micruxpurmn uurlonini ATCC 9079 50 Micrusporum (unis ATCC 10241 50Triclmplrvlvn me!nagrup/lymr 50 (gypseum) ATCC 9129 TricIwp/zymnmenmgropllyu'x 50 (intcrdigitalc) ATCC 9972 'IrivIwp/rvron munmgruphyu's50 (asteroidcs) ATCC 8757 Candida ulhimns ATCC 10231 100 By substitutionof B-methyl-8-methylene-1-(3- methylcyclopentene)-l-pentanoic acid orBmethyl-8- methylene-1-(4-methylcyclopentene)1-pentanoic acid forii-methylene-l-cyc1opentene-1-pentanoic acid in v the above procedurethere is obtained respectfully wherein R is hydrogen or methyl with theproviso that whenever R is methyl the R'-cyclopentenyl radical isselected from the group consisting of 3-methyl-1- cyclopentenyl and4-methyl-1-cyclopentenyl.

2. The compound according to claim 1 which is e-methylene 1-cyclopentenel -pentanol.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF DIENE ALCOHOLS OFTHE FORMULA
 2. The compound according to claim 1 which is epsilon-methylene-1-cyclopentene-1-pentanol.